Anticancer Drug Discovfry Basfd On Biological Fndpoints

Cytotoxicity Assays - Several fermentation-derived compounds with significant antitumor activity were initially identified and isolated in antimicrobial screening programs with subsequent demonstration of mammalian cell toxicity. Notable examples are actinomycins, anthracyclines, bleomycins, and mitosanes. Unfortunately, the number of antimicrobial agents with cytotoxic activity but little or no significant antitumor activity is extensive, and more sophisticated assay methodology is required to select natural products with potential antitumor activity. Nevertheless, novel cytotoxic antibiotics have been isolated and characterized based on antimicrobial activity during the past year. These include 9-methyl-8,9-epoxystreptimidone (1), hataomycin (2), UK-63,052 (3), and spirocardin A and B (4), none of which has been reported to have significant in vivo antitumor activity.

Straightforward cytotoxicity assays with established tumor cell lines continue to be utilized to identify many novel natural products and synthetic agents with potential antitumor activity. It is beyond the scope of this chapter to cite the vast number of novel cytotoxic compounds identified during the past year for which antitumor evaluation has not as yet been reported. However, a number of natural products identified by their cytotoxic activity have recently entered clinical trial. These include the first marine natural product, didemnin B (1), to be evaluated extensively in man (5). This cyclic depsipeptide may be of greater interest as an immunosuppressive agent in transplantation as its preclinical profile in tumor models is not outstanding (6, 7). Mechanistic studies suggest that didemnin B may act as an inhibitor of protein biosynthesis (8). Another natural product of interest both as an antitumor agent and immunosuppressant is deoxyspergualin (2) (9, 10). An analog of 2. was initially discovered in a screen for inhibition of focus formation in Rous sarcoma virus infected chicken fibroblasts (11). Compound 2 is in Phase I clinical trial in cancer patients (12) despite the finding that its preclinical antitumor activity is limited to leukemia models (9); its mechanism of cytotoxic and immunosuppressive activity has not been elucidated. A novel cytotoxic antibiotic recently introduced into clinical trial (13) is elsamicin A (2). This compound demonstrated activity in preclinical leukemia and solid tumor models and would appear to act by binding to DNA(14).

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